The objectives of this proposal are to attempt to define the sequence of events essential for the induction of cancer by known chemical carcinogens in experimental animals. Primary emphasis will be given to the study of the aromatic amine carcinogens and their derivatives, especially 2-acetylaminofluorene and its N-hydroxy metabolite. We propose to study differences in the metabolism, particularly metabolic activation reactions, in susceptible tissues of the rat. Tissues to be examined include liver, mammary gland, and the sebaceous gland of the external auditory canal (Zymbal's gland). The interaction of reactive metabolites of 2-acetylaminofluorene with RNA and DNA in these tissues will be studied in an effort to determine whether or not these reactions are critical in carcinogenesis. Efforts will be made to determine the nature of the mechanisms involved in the progression of the carcinogenic process, especially in liver; e.g., one critical factor appears to be cell proliferation induced by the hepatotoxicity of 2-acetylaminofluorene. BIBLIOGRAPHIC REFERENCES: R. Cox and C.C. Irving. Damage and Repair of DNA in Various Tissues of the Rat Induced by 4-Nitroquinoline-1-oxide. Cancer Research, 35, 1858-1860 (1975). C.C. Irving. Comparative Toxicity of N-Hydroxy-2-acetylaminofluorene in Several Strains of Rats. Cancer Research, 35, 2959-2961 (1975).